Most cytotoxic drugs exhibit undesirable toxic side effects due to their lack of selective action toward the tissues or cells requiring therapeutic effect. Various approaches have been pursued to achieve the selective delivery of cytotoxic agents to a target cell type. Using biological receptor ligands as carriers of drugs to target these drugs to the cells of interest can reduce toxic side-effects and greatly improve the efficiency of drug delivery. For example, Patent Cooperation Treaty (“PCT”) Publication No. WO 97/19954 discloses conjugates of an anthracycline cytotoxic agent such as doxorubicin with a peptide hormone such as LHRH, bombesin or somatostatin. The cytotoxic agent is covalently attached to the peptide via a linker having the structure: —C(O)—(CH2)n—C(O)—, wherein n=0-7.
Similarly, European Patent Application No. EP 1,118,336 discloses conjugates of somatostatin analogs, e.g., octreotide, lanreotide and vapreotide, and a cytotoxic drug, such as paclitaxel, doxorubicin or camptothecin, through a spacer, wherein the spacer is also indicated to have the structure: —C(O)—(CH2)n—C(O)—, wherein n=0-7.
U.S. Patent Application Publication No. 2002/0115596 discloses conjugates of cytotoxic agents and oligopeptides in which the amino acid sequences of the peptides are indicated to be cleaved preferentially by free prostate specific antigen. Such conjugates are said to be useful for the treatment of prostate cancer and benign prostatic hyperplasia.
U.S. Patent Application Publication No. 2003/0064984 discloses conjugates of cytotoxic analogs of CC-1065 and the duocarmycins with cleavable linker arms and a targeting agent such as an antibody or a peptide. The cytotoxic analogs are indicated to be released upon cleavage of the linker.
PCT Publication No. WO 02/34237 discloses conjugates of active agents covalently attached directly to a polypeptide. The polypeptide is said to stabilize the active agent, e.g., in the stomach, through conformational protection.
There remains, however, a significant need for targeted cytotoxic drugs with improved properties with respect to targeting specificity, systemic toxicity and pharmacokinetics.
The application of targeted cytotoxic compounds is contemplated to aid in the treatment of a number of cancerous diseases or conditions. For example, treatment of tumors or cancers which over-express neuropeptide Y (“NPY”) receptors are contemplated to be targeted and treated by native human neuropeptide Y (“hNPY”), i.e., H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH2 (SEQ ID NO:1), or a fragment or analogue thereof, complexed with a cytotoxic moiety.
The effect of NPY can be mediated by several NPY receptor subtypes, named Y1-Y6, from which Y1, Y2, Y4 and Y5 have been extensively characterized. For a review of NPY and NPY receptors, see, e.g., C. Wahlestedt and D. Reis, Annual Review of Pharmacology and Toxicology, 33:309-352 (1993).
Based on the high density and high incidence of the NPY-Y1 receptor in breast tumor and metastasis samples, as discussed in PCT Publication No. WO 02/43776, breast cancers represent an important target for NPY-related drugs. It was also found that, as discussed in PCT Publication No. WO 02/43776, the neuropeptide Y1 receptor is exclusively expressed on tumor tissue either in combination with the Y2 receptor or alone, whereas healthy tissue only expresses the Y2 receptor. The Y1 receptor binding compound disclosed in PCT Publication No. WO 02/43776 is selected from the group consisting of the following compounds:                “[Leu31, Pro34]-NPY (SEQ ID NO:81), [Leu31, Pro34]-PYY (SEQ ID NO:82), Pro34-NPY (SEQ ID NO:83), Pro34-PYY (SEQ ID NO:84), NPY (SEQ ID NO:1), PYY (SEQ ID NO:80), Des Asn29-[Trp28,32, Nva34]-NPY (27-36) (Balasubramaniam, Peptides 18(3), 445-457 (1997) (SEQ ID NO:85)), [Pro30, Tyr32, Leu34]-NPY (28-36) (Leban et al., J. Med. Chem. 38, 1150-1157 (1995) (SEQ ID NO:86)), the dimer Bis (31/31′){[Cys31, TrP32, Nva34]-NPY (31-36)} (Balasubramaniam, supra, (SEQ ID NO:87)), SR 120819A (Serradeil et al., FEBS lett. 225, 209-214 (1987)), BIBP3236 (Rudolf et al., Eur. J. Pharmacol. 271, R11-R13 (1994)), three compounds described in Daniels et al., Proc. Natl. Acad. Sci. USA 92, 9067-9071 (1995): 383U91 of the formula        
                1120W91 of the formula        
                1229U91 of the formula        
                and arginine mimics.”        
Thus, the ability to target the NPY-Y1 receptor with Y1-selective NPY analogues conjugated to a cytotoxic moiety would aid in the treatment of cancerous diseases or conditions. Such cancers include, but are not limited to, breast cancer, ovarian cancer, glial tumors, renal cell carcinomas, nephroblastoma, and intratumoral blood vessels.
Particular advantages of the compounds of the present invention and uses thereof as treatments of tumors and cancers which represent an important target for NPY-related drugs include, but are not limited to, lessened toxic side effects, increased efficacy of treatment, and/or decreased complications from multi-drug resistance.